title: Proline- and acidic amino acid-rich basic leucine zipper proteins modulate peroxisome proliferator-activated receptor alpha (PPARalpha) activity.
abstract: In mammals, many aspects of metabolism are under circadian control. At least in part, this regulation is achieved by core-clock or clock-controlled transcription factors whose abundance and/or activity oscillate during the day. The clock-controlled proline- and acidic amino acid-rich domain basic leucine zipper proteins D-site-binding protein, thyrotroph embryonic factor, and hepatic leukemia factor have previously been shown to participate in the circadian control of xenobiotic detoxification in liver and other peripheral organs. Here we present genetic and biochemical evidence that the three proline- and acidic amino acid-rich basic leucine zipper proteins also play a key role in circadian lipid metabolism by influencing the rhythmic expression and activity of the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). Our results suggest that, in liver, D-site-binding protein, hepatic leukemia factor, and thyrotroph embryonic factor contribute to the circadian transcription of genes specifying acyl-CoA thioesterases, leading to a cyclic release of fatty acids from thioesters. In turn, the fatty acids act as ligands for PPARα, and the activated PPARα receptor then stimulates the transcription of genes encoding proteins involved in the uptake and/or metabolism of lipids, cholesterol, and glucose metabolism.
authors.affiliation: Department of Molecular Biology, National Center of Competence in Research Frontiers in Genetics, Sciences III, University of Geneva, CH-1211 Geneva 4, Switzerland. frederic.gachon@unil.ch
authors.forename: Frédéric
authors.initials: F
authors.lastname: Gachon
authors.forename: Nicolas
authors.initials: N
authors.lastname: Leuenberger
authors.forename: Thierry
authors.initials: T
authors.lastname: Claudel
authors.forename: Pascal
authors.initials: P
authors.lastname: Gos
authors.forename: Céline
authors.initials: C
authors.lastname: Jouffe
authors.forename: Fabienne
authors.initials: F
authors.lastname: Fleury Olela
authors.forename: Xavier
authors.initials: X
authors.lastname: de Mollerat du Jeu
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli
authors.forename: Ueli
authors.initials: U
authors.lastname: Schibler
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D055106:Genome-Wide Association Study; D005947:Glucose / Q000378:metabolism; D016350:Leucine Zippers; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000096:biosynthesis* / Q000235:genetics; D010170:Palmitoyl-CoA Hydrolase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D015262:Xenobiotics / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D005227:Fatty Acids; D047493:PPAR alpha; D014157:Transcription Factors; D015262:Xenobiotics; D002784:Cholesterol; D010170:Palmitoyl-CoA Hydrolase; D005947:Glucose